The present invention relates to a process for preparing an indole derivative, namely 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxyacetic acid. The process substantially follows a sequence of reaction steps known per se and including the esterification of 1-(chlorobenzoyl)-5-methoxy-2-methylindole-acetic acid with a chloroacetic acid derivative carrying a protective group on its carboxyl group followed by splitting off the protective group.
The 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxyacetic acid, for which the World Health Organization recommends the International Nonproprietary Name acemetacin, is disclosed in German Laying-Open-Specification No. DE 22 34 651 A1 as an antiinflammatory drug representing a valuable modification of 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid, which latter is well introduced and used in the therapeutic practice, and for which the International Nonproprietary Name indomethacin is well accepted.
From the above names of both compounds according to systematic nomenclature acemetacin obviously can be understood to be a derivative of indomethacin resulting from the esterification of the carboxyl group of indomethacin with the .alpha.-hydroxyl group of glycolic acid.
As is obvious for the expert, such as a direct esterification cannot be carried out in practice; instead, glycolic acid must be replaced by a carboxylic acid carrying on its .alpha.-carbon atom especially a chlorine atom instead of the hydroxyl group and a suitable protective group on its carboxy radical the proper choice of the protective group is of paramount importance, since under the reaction conditions used for splitting off this protective group at least the other ester bond of the desired final product is split, too, while additionally other groups or radicals of the quite delicate molecule tend to be modified.
For solving this problem a benzyl radical is used as the protective group in the method disclosed in No. DE 22 34 651 A1. The benzyl radical, when used as a protective group, can be split off with hydrogen ions while simultaneously substantially not effecting the remaining moieties of the molecule.
The aforementioned reference also discloses additional alternative ways for preparing acemetacin which methods do not use indometacin as an intermediate. All these methods, however, have the common feature that the last intermediate in the respective sequence of reaction steps carries a benzyl group protecting the carboxyl group, which benzyl group then must be split off hydrogenolytically in a final reaction step.
The method of hydrogenolytic cleavage, however, implies a considerable technical effort if compared to an ester cleavage via hydrolysis. Also the results obtainable with such cleavage are not really efficient, since under the necessary reaction conditions the chlorine atom of the chlorobenzoyl substituent also is split off, at least partially. In practice, the different methods using hydrogenolytic debenzylation obviously were disadvantageous to such an extend that a few years later a method for producing acemetacin was developed (cf. No. DE 29 43 125 A1) based on a planned and careful synthesis of the indole structure itself, in which method .alpha.-(chlorobenzoyl)-4-methoxyphenylhydrazine hydrochloride is reacted with benzyl levulinate to yield the corresponding hydrazone, which in turn is subject to a cyclocondensation splitting off ammonia, and yielding the desired final product having an unprotected carboxyl group.